New Approaches to Catalyst Screening and Development

催化剂筛选和开发的新方法

• 批准号: 2102705
• 负责人: David Hage
• 金额: $ 57.5万
• 依托单位: University of Nebraska-Lincoln
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2102705&HistoricalAwards=false
• 关键词: New; Approaches; Catalyst; Screening; Development

This research project builds on a platform being developed by the University of Nebraska research team to exploit enzymes as catalytic reporters to facilitate reaction discovery and catalyst optimization. This approach is termed In Situ Enzymatic Screening. The method utilizes ‘reporting enzymes’ to provide real-time information on the relative rates for a set of parallel organic/organometallic reactions of interest. Parallel screening methods are of interest to chemists in academia and industry as they enable the identification of fundamentally new transformations of novel catalysts for targeted reactions. There is a particular need for focused screening in process chemistry groups in the pharmaceutical industry, where reaction optimization is critical. This project seeks to develop new enzymatic screening tools that are applicable across a range of temperatures and that take advantage of phosphate ester functionality for which enzymatic screens are not yet available. The project will also help build the future STEM (science, technology, engineering, and mathematics) workforce by training a diverse group of undergraduate and graduate students in an interdisciplinary research environment at the chemistry/biology interface, including elements of organic, organometallic, analytical, and enzymatic chemistry. This project will further explore and develop an information-rich parallel screening method, termed In Situ Enzymatic Screening (ISES), that uses enzymes as biomacromolecular sensors to provide read-out directly to the experimentalist. This research builds upon the team's earlier proof-of-concept studies that led to the first examples of catalytic asymmetric allylic amination chemistry with nickel, an earth-abundant metal, and that uncovered a useful new transformation for diversity-oriented synthesis known as thiocyanopalladation/carbocyclization. This proposal seeks to fully launch the ‘phosphate-ISES’ and ‘thermal-ISES’ screening platforms. The former goal is motivated by the emergence and importance of substrates bearing dialkyl phosphate functionalities, an important functional group both for transition metal coordination and for specific chemistry. These new enzymatic screening platforms have been built by expressing and testing candidates for screening enzymes that recognize dialkyl phosphates and/or that operate at elevated temperatures. Preliminary results point to enzymes that produce a UV/vis signal under such conditions, enabling the screening of candidate metal-ligand combinations at elevated temperatures or in reactions where dialkyl phosphate functionalities are critical. These methods are being developed with specific targeted chemistry in mind, particularly the catalytic asymmetric synthesis of alpha-halovinyl amino acids as potential mechanism-based inhibitors for PLP (pyridoxal phosphate) enzymes. This synthetic goal builds on recent developments in this laboratory in which quaternary, alpha-(1’-fluoro) vinyl amino acids were synthesized for the first time. The scientific broader impacts of this work include opening new avenues for the catalyst discovery process and for green and sustainable chemistry.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

该研究项目建立在内布拉斯加大学研究团队开发的平台上，利用酶作为催化报告分子，以促进反应发现和催化剂优化。这种方法被称为原位酶筛选。该方法利用“报告酶”提供一组平行的有机/有机金属反应的相对速率的实时信息。平行筛选方法是学术界和工业界化学家感兴趣的，因为它们能够识别用于靶向反应的新型催化剂的全新转化。在制药工业中，反应优化是至关重要的，因此特别需要在工艺化学组中进行集中筛选。该项目旨在开发新的酶筛选工具，这些工具适用于一系列温度，并利用酶筛选尚未提供的磷酸酯功能。该项目还将通过在化学/生物学界面的跨学科研究环境中培训多样化的本科生和研究生群体，包括有机，有机金属，分析和酶化学的元素，帮助建立未来的STEM（科学，技术，工程和数学）劳动力。该项目将进一步探索和开发一种信息丰富的平行筛选方法，称为原位酶筛选（ISES），该方法使用酶作为生物大分子传感器，直接向实验人员提供读数。这项研究建立在该团队早期的概念验证研究的基础上，该研究导致了镍催化不对称烯丙基胺化化学的第一个例子，镍是一种地球上丰富的金属，并且发现了一种有用的新的多样性导向合成转化，称为硫氰基钯化/碳环化。该提案旨在全面启动“磷酸盐ISES”和“热ISES”筛选平台。前一个目标的动机是承载磷酸二烷基酯官能团的底物的出现和重要性，磷酸二烷基酯官能团是过渡金属配位和特定化学的重要官能团。这些新的酶筛选平台已经通过表达和测试用于筛选识别磷酸二烷基酯和/或在高温下操作的酶的候选物而建立。初步结果指出，在这样的条件下产生的UV/维斯信号的酶，使候选金属-配体组合的筛选在高温下或在反应中，磷酸二烷基酯的功能是至关重要的。这些方法正在开发中，考虑到特定的靶向化学，特别是α-卤代乙烯基氨基酸的催化不对称合成，作为PLP（磷酸吡哆醛）酶的潜在机制为基础的抑制剂。这一合成目标建立在该实验室的最新进展基础上，其中首次合成了季α-（1 '-氟）乙烯基氨基酸。这项工作在科学上的广泛影响包括为催化剂发现过程以及绿色和可持续化学开辟了新的途径。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。